9-37592265-A-G

Position:

• chr9-37592265-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001790.3(TOMM5):​c.121+147T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TOMM5 NM_001001790.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.47

Genes affected

TOMM5 (HGNC:31369): (translocase of outer mitochondrial membrane 5) Predicted to be involved in protein targeting to mitochondrion. Located in mitochondrion. Part of mitochondrial outer membrane translocase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07422897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMM5	NM_001001790.3	c.121+147T>C		intron_variant		ENST00000321301.7	NP_001001790.1
TOMM5	NM_001134484.2	c.268T>C	p.Cys90Arg	missense_variant	1/2		NP_001127956.1
TOMM5	NM_001134485.2	c.223+45T>C		intron_variant			NP_001127957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMM5	ENST00000321301.7	c.121+147T>C		intron_variant		1	NM_001001790.3	ENSP00000313584	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398538 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The c.268T>C (p.C90R) alteration is located in exon 1 (coding exon 1) of the TOMM5 gene. This alteration results from a T to C substitution at nucleotide position 268, causing the cysteine (C) at amino acid position 90 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.0
DANN	Benign	0.37
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Vest4		0.071
MutPred		0.38		Gain of MoRF binding (P = 0);
MVP		0.043
MPC		1.3
ClinPred		0.20	T
GERP RS		-8.4
gMVP		0.060

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1412916885; hg19: chr9-37592262;